Page 753 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 53 Juvenile Idiopathic Arthritis 725

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Using linkage and association studies, researchers have identi- found in a partially overlapping subset of children with RF
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fied a variety of potentially JIA-associated genes. However, outside poly-JIA. Thus a variety of autoantibodies are associated with
of the HLA genes, only a small percentage of these genes have JIA.
been independently confirmed by other investigators. A few of
the independently confirmed JIA-associated genes/gene products T-Helper Cells
include PTPN22 (a phosphatase involved in inhibition of T-cell T lymphocytes are also thought to play a major role in the
activation), WISP3 (a signaling protein), interleukin-1α (a development of JIA as evidenced by their relative predominance
proinflammatory cytokine), TNF (another proinflammatory among mononuclear cells in synovial fluid of chronically inflamed
cytokine), macrophage migratory inhibitory factor (MIF), and joints in children with JIA. CD4 T-helper (Th) cells have been
SLC11A1 (a resistance factor to intracellular pathogens in categorized into a variety of cytokine-producing subsets (Chapter
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macrophages). Thus gene products linked to both innate and 16). CD4 Th1 cells characterized by the production of interferon-γ
adaptive immune responses likely contribute to JIA disease (IFN-γ) have been identified in chronically inflamed joints in
susceptibility. Ongoing GWAS may help validate the importance children with JIA, whereas IL-4–producing Th2 CD4 T cells are
of these genes and may identify other candidate gene risk factors more commonly involved in the joints in oligoarticular JIA
for JIA in the near future. Recently, epigenetic (modifications (generally less aggressive arthritis) than in polyarticular JIA. More
to DNA nucleotides rather than changes in the DNA sequence) recently, two relatively newly described CD4 Th subsets, regulatory
risk factors that confer susceptibility to JIA are beginning to be T cells (Tregs) and Th17 cells, are being examined as potential
explored. 10 players in JIA pathology.
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CD4 , CD25 high Tregs are characterized by the transcription
ENVIRONMENTAL FACTORS factor, FoxP3, and by the ability to suppress immune activation
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(Chapter 18). The ability of Tregs to suppress other T cells
In addition to genetic factors, there are likely a variety of envi- likely occurs by both cell-contact dependent (through the surface
ronmental triggers for developing JIA in genetically susceptible protein cytotoxic T lymphocyte antigen-4 [CTLA-4]) and
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hosts. A number of infectious agents have been explored as risk independent (via suppressive cytokines) mechanisms. Tregs
factors for development of JIA. Perhaps two of the best studied secrete the antiinflammatory cytokines, IL-10 and transforming
have been parvovirus and rubella virus infections. However, growth factor-β (TGF-β). Th17 cells, characterized by the
replication of these associations has been difficult. In addition, transcription factor, retinoid orphan receptor (ROR)γT, produce
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some scientists have suggested that heat shock proteins, resulting the proinflammatory cytokine, IL-17. IL-17 is thought to
from cells undergoing environmental stress, may contribute to contribute to a variety of autoimmune disorders, including JIA.
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the development of JIA. There is also a clear link between gut The balance between these two juxtaposed Th subsets may
pathogens and potentially commensal organisms (gut microbi- determine whether autoimmunity develops (Th17-dominant)
ome) and the development of HLA-B27–associated spondylo- or a state of immune tolerance to self (Chapter 12) persists
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arthropathies. Last, prior to the identification of Borrelia as a (Treg-dominant). Indeed, recent studies have identified a pre-
cause of childhood arthritis, Lyme disease associated arthritis dominance of Th17 cells and associated proinflammatory
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was difficult to distinguish from oligoarticular JIA. Perhaps cytokines in the inflamed joints of children with JIA. Thus a
because there a variety of potential environmental triggers for balance of proinflammatory cytokines and suppressive cytokines
JIA, combined with the number of different JIA categories, no may dictate the expression of autoimmunity in the form of JIA.
single environmental trigger has been conclusively identified as
contributing to the development of JIA. Cytokines
Cytokines (Chapter 9), and particularly their inhibition, have
IMMUNE ABNORMALITIES taken a prominent status in the pathology and treatment of
chronic arthritis, including JIA. The bench-to-bedside translation
Autoantibodies of anti-TNF therapy to the treatment of chronic arthritis has
As JIA is considered an autoimmune disease, except for sJIA as revolutionized the care of adults with chronic arthritis, as well as
discussed earlier, there have been a variety of explorations into children with JIA. Inhibition of this proinflammatory cytokine
the role of various components of the immune system involved in the circulation (via specific monoclonal antibodies [mAb]
in JIA pathogenesis. The importance of the immune system in or receptor fusion proteins) rapidly and effectively treats most
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JIA pathology is highlighted by the increased incidence of child- forms of JIA. The one exception is sJIA, which may or may not
hood chronic arthritis among children with various immuno- respond to anti-TNF treatment. However, other proinflammatory
deficiencies. For example, children with immunoglobulin A (IgA) cytokines, including IL-1, -6, and -18, are thought to be central to
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deficiency are at increased risk of developing chronic arthritis. sJIA pathogenesis. Indeed, serum from sJIA patients was shown
In contrast, the presence of specific autoantibodies is associated to induce transcription of a variety of innate immunity genes,
with various forms of JIA. ANAs are present in up to 40% of including IL-1, in normal peripheral blood mononuclear cells.
patients with JIA, particularly those with oligoarticular JIA and Fortunately, novel therapies that target either IL-1 or IL-6 have
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are associated with silent uveitis (Chapter 74). Similarly, antibod- proven highly successful in treating even the most severe forms
ies to the nuclear oncoprotein DEK have been associated with of sJIA, including associated macrophage activation syndrome
uveitis as well as joint inflammation in children with JIA. IgM (MAS). 1,7
rheumatoid factor (RF) is present in a smaller subset of children
with polyarticular JIA and is associated with a more aggressive/ Macrophage Activation Syndrome
erosive form of arthritis as in adults with rheumatoid factor– The sometimes fatal complication MAS is most commonly seen
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positive (RF ) RA (Chapter 52). More recently, identification in sJIA among rheumatic diseases. Clinically, MAS resembles
of anti–cyclic citrullinated peptide (CCP) antibodies have been many features of a sJIA disease flare-up, and it has been suggested